Physical activity and exercise cause mechanical strain to occur within bone, thereby initiating an adaptive osteogenic response. Owing to this process, exercise during growth and young adulthood has been shown to increase peak bone mass and improve bone mechanical properties, providing life-long protection against osteoporosis. In animals, mechanical strain magnitude and strain rate are two key variables that are related to the degree of bone adaptation, with increasing osteogenic response occurring as each of these variables increases. Although the same mechanisms likely influence bone adaptation in humans, the manner in which this animal data may be translated has not been rigorously tested. The objective of this application is to quantitatively define, for the first tim in humans, the relationship between strain magnitude and strain rate to changes in distal radius bone structure and strength. Our global hypothesis is that larger strain magnitudes and rates will elicit a greater osteogenic response. This hypothesis is based on similar relationships that have been described in rodent loading models. Similarly, we hypothesize that local regions experiencing high strain magnitudes or rates within a bone will experience local increases in bone density, and that high levels of physical activity, strength, or bone mass may decrease the osteogenic response. Our rationale is that osteoporosis can be most effectively addressed with prevention, and the knowledge gained is essential so that future clinical trials of exercise to improve bone health can be systematically designed to maximize the potential effect of the intervention. We have developed a simple in vivo human loading model in which subjects apply a force to the radius by leaning onto the palm of the hand, and we have validated noninvasive methods to quantify strain magnitude and rate, bone strength, and bone structure within this site. Using this model, we propose three aims to test the relationship between bone adaptive response and bone mechanical strain environment. The first two aims are each independent 12-month randomized clinical experiments that include two experimental groups and one control group (20 subjects per group, for 60 subjects per aim). For the first aim, strain magnitude will be assigned as either low (1800 me) or high (3600 me) at a constant strain rate. For the second aim, strain rate will be assigned as either low (4500 me/s) or high (36,000 me/s) at a constant strain magnitude. In each of these aims women will apply three bouts of loading to their radii per week for 12 months (156 bouts total) and changes to bone structure and strength will be measured using quantitative computed tomography and subject-specific finite element models. The third aim is the 12-month follow-up of subjects enrolled in Aims 1 and 2. The research is novel because it directly translates relationships previously demonstrated in animals to humans. The research is innovative in its use of noninvasive methods to characterize loading exposure and bone strength. PUBLIC HEALTH RELEVANCE: The proposed project examines the relationship between mechanical signals applied to the forearm of women, and the resulting improvements to forearm bone strength and structure. Similar studies have been undertaken in small animals, but this project is the first to rigorously test this relationship in humans. By understanding the input/output relationship between mechanical signals (input) and bone improvements (output), exercises can be developed to maximally improve bone health, thereby preventing osteoporosis and fractures.